Isoflavone metabolites possess a very wide range of important biological properties including oestrogenic effects (WO 98/08503). Isoflavone metabolites can be isolated from the urine of human volunteers subjected to diets rich in plant isoflavanoids such as soya, lentils, peas and beans.
In spite of the recently discovered biological significance of isoflavone metabolites there is not at present a general method suitable for the large scale synthesis of these metabolites. The few reported syntheses of these metabolites utilise either catalytic hydrogenation or hydrogen transfer reduction of the corresponding isoflavones. These reduction reactions are found to be non-selective, extremely difficult to control and lead to mixtures of different products.
The reduction of 5,7-dihydroxyisoflavylium salts have been reported to give mixtures of isoflav-2-enes, isoflav-3-enes and isoflavans. The individual compounds are difficult to separate and can be obtained only in low yields. Sodium borohydride reductions of isoflavones are known, see Ádám Major et al. Liebigs Ann. Chem. (1988) 555-558, however the reactions are low yielding, typically not clean and substituents on the basic isoflavone ring structure require tedious protective groups not affected by metal hydrides.
Chromatography is often required to separate the reaction products and only low yields of isoflavanones, isoflavan-4-ols, isoflavenes and isoflavans are obtained. The chromatography required is tedious and often impracticable for large scale reactions. Furthermore, attempts to improve the yield and purity of products obtained from hydrogenation reactions has been met with limited success as evidenced by published results which are largely contradictory.
Solvents used in hydrogenation reactions of isoflavones reported in the literature include N-methylpyrrolidinone, see Liepa, A. J., Aust. J. Chem., 1981, 34, 2647-55. However this solvent is unsuitable for pharmaceutical preparations of isoflavone metabolites and derivatives because N-methylpyrrolidinone is a severe eye irritant and a possible carcinogen. Furthermore the high boiling point of the solvent makes it extremely difficult to remove after the reduction.
Isoflavan-4-ols are key intermediates in the synthesis of isoflavenes and accordingly there is a need for more efficient and reliable syntheses of isoflavan-4-ols, or at least comparable alternatives, acceptable than those known in the art. There is also a need for synthetic methods for isoflavone hydrogenation which utilise solvents pharmaceutically more acceptable than those previously reported. Therefore it is an object of the present invention to overcome or at least alleviate one or more of the above-mentioned disadvantages of the prior art. It is an other object of the present invention to synthesise novel isoflavone metabolites and derivatives.
Surprisingly hydrogenation conditions have been found by the present inventors which enable the synthesis of isoflavone derivatives in good to excellent yields. In particular the conditions found by the present inventors allow for the hydrogenation of isoflavones to relatively pure tetrahydroisoflavan-4-ol products in excellent yields, and without the need for pharmaceutically unsuitable solvents and extensive chromatography in the hydrogenation reactions.